(5-nitro-2-furyl)methyl N^ε-(pteroyllysyl)-N,N-bis(2-chloroethyl)phosphorodiamidate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (5-nitro-2-furyl)methyl N^ε-(pteroyllysyl)-N,N-bis(2-chloroethyl)phosphorodiamidate
• 英文别名: (2S)-2-[[4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzoyl]amino]-6-[[bis(2-chloroethyl)amino-[(5-nitrofuran-2-yl)methoxy]phosphoryl]amino]hexanoic acid
• 化学式: C₂₉H₃₅Cl₂N₁₀O₉P
• 分子量: 769.538
• InChiKey: BDKGHEJNDGNCIT-SOQGBTOKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  51
• 可旋转键数：
  20
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  272
• 氢给体数：
  6
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  N10-三氟乙酰基蝶酸 在 potassium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 147.0h， 生成 (5-nitro-2-furyl)methyl N^ε-(pteroyllysyl)-N,N-bis(2-chloroethyl)phosphorodiamidate
  参考文献：
  名称：

  Synthesis and Evaluation of Pteroic Acid-Conjugated Nitroheterocyclic Phosphoramidates as Folate Receptor-Targeted Alkylating Agents

  摘要：

  A novel nitroheterocyclic bis(haloethyl)phosphoramidate prodrug linked through lysine to a pteroic acid has been prepared and evaluated as a potential alkylating agent, to target tumor cells that overexpress the folate receptor. The prodrug exhibited IC50 values in the micromolar range and was 10-400-fold less cytotoxic in vitro than the phosphoramidate that lacks the lysine-pteroyl moiety. The data does not support a contribution of the folate receptor to cytotoxicity. In an attempt to determine the basis for the decreased cytotoxicity in the pteroyl-lysyl analogue, compounds were prepared in which the lysine-pteroyl moiety was replaced with lysine alone or with an n-propyl group. The n-propyl and the lysyl analogues were on average 3.8- and 21-fold less potent than the unsubstituted bis(haloethyl)phosphoramidate, respectively. Chemical reduction of the prodrugs followed by P-31 NMR kinetics demonstrated that all of the phosphoramidate anions cyclized to the aziridinium ion at similar rates and gave comparable product distributions, suggesting that changes in chemical activation did not account for the differences in cytotoxicity. It, is likely that folate receptor-mediated transport is not sufficient to deliver adequate intracellular concentrations of the cytotoxic phosphoramide mustard.

  DOI：

  10.1021/jm000306g

文献信息

• PHOSPHORAMIDITE DERIVATIVES OF FOLIC ACID
  申请人：Barta Nancy Sue

  公开号：US20120035362A1

  公开（公告）日：2012-02-09

  The present invention provides for compounds of Formula I: wherein L and R 1 -R 6 have any of the values defined there for in the specification. The compounds of formula I are useful as reagents to form folic acid conjugates with hydroxyl-containing compounds of interest, such as oligonucleotides and anti-cancer compounds.

  本发明提供了I式化合物：其中L和R1-R6的任何值均在说明书中定义。I式化合物可用作试剂，与感兴趣的羟基含有化合物如寡核苷酸和抗癌化合物形成叶酸共轭物。
• [EN] PHOSPHORAMIDITE DERIVATIVES OF FOLIC ACID<br/>[FR] DÉRIVÉS D'ACIDE FOLIQUE À BASE DE PHOSPHORAMIDITE
  申请人：BERRY AND ASSOCIATES INC

  公开号：WO2012018729A1

  公开（公告）日：2012-02-09

  The present invention provides for compounds of Formula (I): wherein L and R1-R6 have any of the values defined there for in the specification. The compounds of formula I are useful as reagents to form folic acid conjugates with hydroxyl- containing compounds of interest, such as oligonucleotides and anti-cancer compounds.
• Synthesis and Evaluation of Pteroic Acid-Conjugated Nitroheterocyclic Phosphoramidates as Folate Receptor-Targeted Alkylating Agents
  作者：Gali Steinberg、Richard F. Borch

  DOI：10.1021/jm000306g

  日期：2001.1.1

  A novel nitroheterocyclic bis(haloethyl)phosphoramidate prodrug linked through lysine to a pteroic acid has been prepared and evaluated as a potential alkylating agent, to target tumor cells that overexpress the folate receptor. The prodrug exhibited IC50 values in the micromolar range and was 10-400-fold less cytotoxic in vitro than the phosphoramidate that lacks the lysine-pteroyl moiety. The data does not support a contribution of the folate receptor to cytotoxicity. In an attempt to determine the basis for the decreased cytotoxicity in the pteroyl-lysyl analogue, compounds were prepared in which the lysine-pteroyl moiety was replaced with lysine alone or with an n-propyl group. The n-propyl and the lysyl analogues were on average 3.8- and 21-fold less potent than the unsubstituted bis(haloethyl)phosphoramidate, respectively. Chemical reduction of the prodrugs followed by P-31 NMR kinetics demonstrated that all of the phosphoramidate anions cyclized to the aziridinium ion at similar rates and gave comparable product distributions, suggesting that changes in chemical activation did not account for the differences in cytotoxicity. It, is likely that folate receptor-mediated transport is not sufficient to deliver adequate intracellular concentrations of the cytotoxic phosphoramide mustard.